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Biology of
Mood & Anxiety Disorders
REVIEW
Open Access
Somatic therapies for treatment-resistant
depression: ECT, TMS, VNS, DBS
Cristina Cusin* and Darin D Dougherty
Abstract
The field of non-pharmacological therapies for treatment resistant depression (TRD) is rapidly evolving and new
somatic therapies are valuable options for patients who have failed numerous other treatments. A major challenge
for clinicians (and patients alike) is how to integrate the results from published clinical trials in the clinical
decision-making process.
We reviewed the literature for articles reporting results for clinical trials in particular efficacy data, contraindications
and side effects of somatic therapies including electroconvulsive therapy (ECT), transcranial magnetic stimulation
(TMS), vagal nerve stimulation (VNS) and deep brain stimulation (DBS). Each of these devices has an indication for
patients with different level of treatment resistance, based on acuteness of illness, likelihood of response, costs and
associated risks. ECT is widely available and its effects are relatively rapid in severe TRD, but its cognitive adverse
effects may be cumbersome. TMS is safe and well tolerated, and it has been approved by FDA for adults who have
failed to respond to one antidepressant, but its use in TRD is still controversial as it is not supported by rigorous
double-blind randomized clinical trials. The options requiring surgical approach are VNS and DBS. VNS has been
FDA-approved for TRD, however it is not indicated for management of acute illness. DBS for TRD is still an
experimental area of investigation and double-blind clinical trials are underway.
Keywords: Treatment resistant depression, Electroconvulsive therapy, Transcranial magnetic stimulation, Vagal
Nerve Stimulation, Deep brain stimulation
Introduction
Major depressive disorder (MDD) affects approximately
18 million people at any one time in the US alone, with
a 17.1% lifetime incidence, and is associated with a high
rate of morbidity and mortality [1].
Pharmacotherapy is effective in more than half of
depressed patients; however, between 20% and 30% of
patients suffering from depression may have “treatmentresistant depression” (TRD).
A recent review [2] compared five different models for
classifying TRD, evolving from simply rating the adequacy of antidepressant trials to considering a more
complex array of factors, including duration of illness,
severity and treatment response. However, the validity
and reliability of those models have been the focus of
only a few studies, and their value for predicting outcome in clinical practice is still unclear.
* Correspondence: [email protected]
Division of Neurotherapeutics, Department of Psychiatry, Massachusetts
General Hospital, 149 13th Street, Rm 2612, Charlestown, MA 02129, USA
The aim of this paper is to review new somatic therapies utilized in the treatment of TRD (defined broadly as
failure to respond to two or more adequate trials of antidepressants in the current episode) in comparison with
electroconvulsive therapy (ECT), considered the “gold
standard” for patients with TRD.
Methods
A literature search was performed using PubMed, Ovid
Medline, Cochrane Database of Systematic Reviews and
PsychINFO for articles published between 1990 and July
2011 with the following search terms: ECT or electroconvulsive therapy, transcranial magnetic stimulation, TMS,
depression, treatment-resistant depression, VNS or vagal
nerve stimulation, DBS or deep brain stimulation, clinical trial. Out of 807 articles retrieved, we included articles written in English that reported clinical trial results
of an original sample, and 98 articles were ultimately
reviewed in detail. The reference sections of the articles
were checked for cross-references. For ECT, we included
© 2012 Cusin and Dougherty; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
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only the studies comparing efficacy of ECT with other
devices. For DBS, given the absence of randomized controlled trials, we included all clinical trials and case
reports.
Results
Electroconvulsive Therapy (ECT)
ECT consists of the application of an electric stimulus to
the surface of the head, with the aim of inducing a seizure. The parameters of the stimulus can vary widely
(pulsewidth from 0.3 to 1 msec, frequency from 20 to
120 Hz, duration of the stimulus 0.5-8 sec) and are
adjusted for each individual patient, according to seizure
threshold, clinical efficacy and side effects. The clinical
efficacy of ECT in TRD is well established, with 60% to
90% rate of acute response in TRD [3], and it is indicated specifically in severe psychotic depression, catatonia and delirious mania.
ECT is associated with a number of common, but usually temporary, adverse effects such as arrhythmias,
headaches, muscle aches, and nausea. Serious medical
complications are exceedingly rare, even in patients with
severe cardiovascular risk factors. The most common
adverse effect of ECT is acute cognitive impairment lasting from few minutes to few days [4] or some form of
amnesia, either anterograde or retrograde. More persistent deficits seem to be associated with older age, sine
wave stimulation and bitemporal electrode placement
[5]. The treatment is administered two to three times
per week, and the patient requires an escort, due to driving restrictions after the treatment. ECT is available in
academic and community settings, and the cost for each
treatment session generally includes fees for the psychiatrist administering the treatment, the anesthesiologist,
and the facility where the treatment is delivered. Although these costs vary considerably across centers, a
course of 10 outpatient ECT treatments can cost approximately $10,000 to $15,000.
Transcranial Magnetic Stimulation (TMS)
Transcranial magnetic stimulation (TMS) was introduced in 1985 as a technique to stimulate the cerebral
cortex non-invasively [6]. A TMS device generates a
strong magnetic field, inducing an electric current in a
specific area, and this in turn induces intracerebral currents in associated neural circuits. The “single pulse
TMS” has been utilized in research on localization of
brain functions, while “repetitive TMS” (rTMS) has
been used for treatment related studies. It is called
“high frequency rTMS” if the stimulus frequency is
above 1 Hz, or "low frequency rTM" if stimulus frequency is below 1 Hz. Low frequency rTMS is thought
to inhibit cortical firing, while high frequency rTMS is
thought to activate it.
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The initial application of rTMS for depression was
driven by functional imaging data showing reduced activity in the left prefrontal cortex (L DLPF) in patients
with depression [7,8]. More recently, the investigators
have focused on the idea of an imbalance in the activity
of the frontal lobes (hypoactivity in the left frontal lobe
and excessive inhibitory activity in the right frontal lobe),
therefore leading to an alternative pattern for the treatment of depression combining low-frequency (suppressive) rTMS of the right dorso-lateral prefrontal cortex
(R DLPF) with rTMS at high frequency to the L DLPF.
TMS is a non-invasive technique, therefore not requiring anesthesia or driving restrictions, and it is safely performed as an outpatient procedure. In general, TMS is
well tolerated, with no evidence of cognitive impairment
and with exceedingly rare medical complications. Rare
seizures have been reported in the past, but the risk is
substantially decreased with current treatment guidelines. The most common adverse effects are headaches
and facial pain. A therapeutic TMS course of treatments
can be performed by a trained technician, and a typical
TMS session lasts between 30 and 60 minutes; sessions
take place 5 times a week, usually for a period of 4 to 5
weeks, for a total of 20 to 30 sessions. One of the major
obstacles is the time commitment for patients, which
entails daily visits of one to two hours to the facility
where TMS is provided. The average cost of each session
is between $300 and $400, leading to a total cost for an
average course of TMS between $6,000 and $12,000.
Efficacy of TMS
Several meta-analyses of rTMS clinical trials have been
published in the past ten years, with mixed results. The
majority of TMS trials targeted the L DLPC with highfrequency stimulation, while only a few targeted the R
DLPC with either low-frequency stimulation [9-11] or
both [12-16]. The earliest meta-analysis [17] yielded a
positive result for rTMS compared to a sham control;
however, it included only five controlled studies and
excluded the only negative depression trial for rTMS
that had been published at the time [18].
In 2002, Martin and colleagues published a Cochrane
review of all the TMS studies available to that date [19].
The authors found that high-frequency (> 1 Hz) prefrontal DLPF rTMS and low-frequency (≤ 1 Hz) R DLPF
rTMS were statistically superior to a sham comparison,
but only at one time point (immediately after two weeks
of treatment), and this difference was not sustained two
weeks later. The overall difference between active and
sham treatment was not large, though statistically significant, and the authors concluded that there was “no
strong evidence to support the benefit of rTMS as an
antidepressant treatment.” Only one meta-analysis,
which included 6 trials, found a negative result for
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high-frequency prefrontal DLPF rTMS compared to
sham [20].
The largest controlled study was sponsored by a TMS
equipment manufacturer and involved a double-blind,
multisite trial with 301 medication-free patients with
MDD who had not benefited from prior treatments.
Subjects were randomly assigned to either active
(n = 155) or sham TMS (n = 146) conditions [21]. The
study found that active TMS was significantly superior
to sham TMS at weeks 4 and 6, and its results were the
basis for the Food and Drug Administration’s (FDA) approval of TMS for patients who had not improved following one antidepressant trial.
The most recent meta-analysis [22] included 34 clinical
trials comparing rTMS to sham treatment. This analysis
showed a statistically significant difference; however,
other papers critically analyzed the methods applied in
the clinical trials [23-25] and suggested that though the
results showed strong statistical evidence of efficacy, the
clinical results were not sufficient to recommend the
implementation of TMS in clinical practice because of
the methodological limitations and heterogeneity of the
studies.
In fact, while the application site of TMS was the L
DLPF in more than 90% of the studies, the stimulation
parameters were extremely variable and the level of severity of the patients enrolled was generally low, as only
3 out of 34 studies included patients who had failed 2 or
more antidepressants in the current episode.
To address those criticisms, the NIH sponsored a large
multicenter study in 2009 [26]. In this trial, the parameters of rTMS were standardized to maximize the likelihood of robust antidepressant effect (five times per
week with TMS at 10 Hz, 120% of motor threshold,
3000 pulses/session, for 4-6 weeks) and key methodological limitations were addressed (e.g., adequacy of
masking, validity of sham treatment, training of raters
and reliability of outcome evaluation, magnetic resonance imaging adjustment for proper scalp placement).
The results of the primary efficacy analysis revealed a
significant difference in the proportion of remitters
(14.1% on rTMS versus 5.1% sham, p = .02); however, the
total number of responders (n = 19) and remitters
(n = 18) was overall very low and the number needed to
treat (NNT) was 10. It is notable that in this study, as in
the previous ones, most of the remitters had low antidepressant treatment resistance at the time of study
entry.
Efficacy of TMS IN TRD
A few studies have investigated the use of TMS in
patients with TRD specifically, usually in combination
with antidepressant drugs. Overall the results reported
have been positive, but it is very difficult to draw any
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conclusion because of small sample sizes, differing inclusion criteria (i.e., inclusion of patients with bipolar depression), variable treatment schedule and high dropout
rate. Three were small open-label studies [27-29], and
one was double-blind, sham-controlled study of the
combination of TMS and escitalopram [30]. In all the
aforementioned studies, the level of treatment resistance
was low, and only one trial randomized patients with
different levels of resistance to unilateral TMS, bilateral
or sham [31]. Based on published data, the role for TMS
in the treatment of TRD is still unclear.
TMS comparison with ECT
One question that is particularly relevant for the clinician is how TMS compares to ECT in patients with
TRD. There have been six prospective studies to date
comparing TMS and ECT in patients with a major depressive episode (MDD or bipolar depression) [32-37].
The sample size in each study was usually small, between 25 and 42 patients, and out of those six, three
studies indicated superiority for ECT and three found no
difference between the two devices. The results were
reviewed in a meta-analysis, including a total of 113
TMS patients and 102 ECT patients, yielding a combined 38.0% rate of response or remission rate for TMS
versus 58.8% for ECT. This resulted in a highly significant
difference in favor of ECT (chi sq = 9.267, p = 0.0023) [38].
Major criticisms common to all these studies were that
they generally utilized low energy and low frequency for
both ECT and TMS, included patients with psychotic features, and did not adequately describe blinding techniques. Despite these limitations, it seems that ECT has
superior efficacy, in particular for those patients with severe depression, psychotic features and higher level of
treatment-resistance.
TMS summary
In 2008, the U.S. FDA approved rTMS as a treatment
for adults with MDD who “have not responded to a single antidepressant medication in the current episode.”
Since then, one large NIMH-sponsored, multicenter,
randomized, sham-controlled study has been conducted
[26], and this trial showed a statistically significant difference between the treatments, but overall low rates for
both response and remission.
In general, TMS is indicated in adults with MDD who
“have not responded to a single antidepressant medication in the current episode.” However, numerous questions still persist about the magnitude of the efficacy of
TMS in patients with TRD.
Due to concerns that the antidepressant effects of
rTMS are not sufficiently robust to be considered "clinically meaningful," insurance companies have often been
reluctant to reimburse for TMS treatment
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Vagal Nerve Stimulation (VNS)
Vagal Nerve Stimulation (VNS) was approved for
treatment-refractory epilepsy in Europe in 1994 and in the
US in 1997. Early clinical observations of improvement of
mood symptoms in epilepsy patients led to a pilot study of
VNS on mood in patients with primary diagnosis of epilepsy. The Cyberonics VNS device currently available on
the market consists of a titanium-encased lithium battery,
a lead wire system with electrodes, and an anchor tether
to secure leads to the vagus nerve. The generator is
implanted in the left chest wall and connected with a lead
to the left vagus nerve. The device is implanted in a procedure usually lasting 1 to 2 hours, either under local or
general anesthesia. Following the surgery, the device is
activated telemetrically by a wand connected to a handheld computerized device. The adjustment of treatment
parameters, including selection of stimulus intensity, duration and on/off interval, is non-invasive and is performed
using an external telemetric wand. Stimulator settings are
programmed to deliver intermittent stimulation with a
current of 0.25–3.0 mA, a frequency of 20–50 Hz, a pulse
width of 130-500 ms, and duty cycle (e.g. 30 seconds on, 5
minutes off). The mechanism of action of VNS is not
completely understood and its effects are thought to be
relatively slow, in the order of months; for this reason,
VNS is not indicated for the relief of acute depressive
exacerbations.
The safety of VNS is well established from its use in
the treatment of epilepsy. The side effects of VNS are
generally mild and are associated with stimulation (i.e.,
the “on” phase of the cycle). Because VNS causes stimulation of the superior and recurrent laryngeal nerves, it
is frequently associated with problems ranging from alteration of the voice, coughing, throat pain and hoarseness (very common), reversible bradyarrhythmias and
obstructive sleep apnea. Infections associated with the
hardware are infrequent but possible. Regarding psychiatric adverse effects, the rate of stimulation-induced
switch to mania or hypomania in the VNS trials was low
in the pivotal trial by Rush and colleagues [39] (<0.01%
at one year), and those symptoms subsided with adjustment of stimulation parameters.
VNS Efficacy IN TRD
In psychiatry, VNS has been developed primarily as adjunctive therapy for patients with TRD who have failed
to respond or have declined ECT; therefore, no comparison with ECT is available. The first open-label trial of
VNS in depression enrolled 30 patients with a major depressive episode (MDD or bipolar depression) who had
failed at least two adequate antidepressant trials (the
average number of failed trials was 4.8 ± 2.7). VNS was
used as augmentation strategy, and the subjects received
10 weeks of stimulation in combination with their
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medication regimen. The results at 10 weeks were a response rate of 40% and a remission rate of 17% [40].
The second pilot study combined the initial study cohort with another sample of 30 patients, followed for 12
weeks, and obtained a response rate of 30% and remission of 15% [41]. The higher degree of treatment resistance in the second pilot study may have been a
significant factor in the less favorable outcome. Similar
results were reported by Schlaepfer and colleagues in an
open-label European study including 74 patients [42].
The striking finding in the long-term follow-up of both
those studies was the apparent increase over time in response and remission rates [43,44].
The largest (n =235) randomized, sham-controlled,
multicenter study of adjunctive VNS, which enrolled
patients with higher level of treatment-resistance (failed
to respond to two or more monotherapies and two augmentations, failure to respond to ECT), did not find a
significant difference between active and sham groups at
12 weeks (15% and 10%, for response and remission respectively) [39]. However, follow-up observations of this
cohort suggested a cumulative beneficial effect of treatment over time, reaching response rates between 27%
and 34% and remission of 15% at one year [45], with
similar outcomes for patients with MDD and BP depression [46]. It is very interesting that in the long term follow-up, the authors reported a decline in suicide
attempts, diminished levels of suicidal ideation, and
fewer hospitalizations for depression in patients with
VNS compared with patients with the same level of
symptom severity but taking medications [47].
Overall the number needed to treat (NNT) for VNS
ranged from 4 to 10, which, given the level of treatment
resistance in this population, is clinically significant. In
2005, based on the clinical trial data, the FDA approved
the use of VNS as an adjunctive therapy for treatmentresistant depression in adult patients who have failed 4
or more medications. Unfortunately the same data were
deemed insufficient for approval of reimbursement
under Medicare/Medicaid, therefore seriously limiting
the access of patients to VNS.
The estimated cost for the surgical implantation of
VNS in day surgery is on the order of $40,000 to
$45.000. Furthermore, this estimate does not include the
cost of post-operative device adjustments ($350-$620),
which are rather frequent at the beginning of treatment
and may significantly impact the total costs of the
treatment.
VNS summary
The safety of VNS is well established from its use in the
treatment of epilepsy for almost two decades, and it
appears to be effective in patients with MDD or Bipolar
II disorder with low to moderate, but not extreme,
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antidepressant resistance. VNS is usually considered as
an adjunct to pharmacologic treatment, and it can safely
be combined with ECT in case of an acute relapse. Because its effects take much longer to appear compared
to antidepressants or ECT, VNS cannot be considered a
treatment for acute TRD. The major barriers preventing
its diffusion in clinical practice of this device are the elevated cost and the lack of reimbursement by insurance
providers in the US at present.
Deep Brain Stimulation (DBS)
DBS is a reversible neurosurgical procedure, consisting
of implanting electrodes at specific anatomical locations
and delivering an electrical impulse of variable intensity
and frequency through those electrodes. DBS is thought
to induce an electrical field that alters complex firing
patterns of the neurons and thus modifies activity in
the neuronal circuits. DBS has been utilized for
treatment-refractory essential tremor and is approved
for Parkinson’s disease [48] and dystonia. In 2009, DBS
was approved for treatment of otherwise intractable
obsessive-compulsive disorder (OCD) in Europe and in
US.
Since the early 1960s, it has been observed that both
acute and chronic stimulation could induce mood
changes, including hypomania, dysphoria, and anhedonia. These observations led to the development of clinical trials to test the possible efficacy of DBS in
treatment-refractory mood disorders. A number of research groups are currently investigating different sites
for implantation of electrodes (for a complete review see
[49]).
1. Subcingulate –Broadmann area 25 (SCG 25) Mayberg and colleagues have demonstrated the
integral role of the subgenual cingulate cortex in
both normal and pathological shifts in mood [50].
Moreover, other studies have indicated an association
between a clinical response to antidepressants and
decrease in metabolism in limbic and striatal areas
(subgenual cingulate cortex, hippocampus, insula,
and pallidum) and increase in metabolism in dorsal
cortical areas (prefrontal, parietal, anterior, and
posterior cingulate cortex).
2. Ventral anterior internal capsule/ventral striatum
(VC/VS) - The dorsal and ventral prefrontal cortex
(PFC) have been found to be dysfunctional in
neuroimaging studies of patients with MDD. These
regions are nodes in a corticostriatalthalamocortical
(CSTC) circuit that also includes components of the
striatum and thalamus. The VC/VS target for DBS
was developed following studies of gamma-knife
capsulotomy for obsessive-compulsive disorder
(OCD) and investigated in early studies by Nuttin
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[51] and Greenberg [52]. In those patients with
primary OCD, a significant improvement was
noticed in depressive symptoms, leading to the
investigation of this target in MDD. Functional
neuroimaging studies in DBS subjects showed
activation of the ventral pre-frontal cortex,
striatum, and thalamus during acute stimulation
of the VC/VS target [53].
3. Nucleus accumbens (NAC) and ventral striatum The reward circuitry of the ventral striatum and
NAC has been associated with drug addiction and
depression. The NAC and ventral striatum receive
projections primarily from the anterior cingulate
cortex, insular cortex, and orbitofrontal cortex. The
NAC then projects to the dorsomedial nucleus of the
thalamus by way of the ventral tegmental area,
ventral pallidum, and substantia nigra—which in turn
projects back to the prefrontal cortex, orbitofrontal
cortex, anterior cingulate cortex, amygdala, and
hypothalamus; this forms the limbic loop of the basal
ganglia [54].
4. Inferior thalamic peduncle (ITP) - The ITP is a
bundle of fibers that connects the thalamic system to
the orbitofrontal cortex. This system is thought to
induce electrocortical synchronization and to allow
the inhibition of irrelevant stimuli, thus allowing
selective attention. The ITP has been identified by
Velasco and colleagues [55] as a potential stimulation
target for TRD. At present there is only one case
report of successful DBS electrode implantation in
the ITP for refractory depression [56].
5. Lateral habenula (LH) - The LH has been proposed
as a putative target for DBS. The habenular nuclear
complex projects to the locus ceruleus, medial dorsal
frontal cortex, orbitofrontal cortex, insula and
mesolimbic areas, and ventral tegmentum/brainstem.
At present there is one case report of DBS at the LH
for MDD [57].
Implantation of DBS
The implantation of DBS electrodes and batteries is a
complex neurosurgical procedure. Under stereotactic
guidance, two electrodes are placed in deep structures of
the brain, relative to a set of anatomical landmarks. Two
programmable neurostimulators are implanted in the
chest area under the clavicle and are connected to the
corresponding electrode by extension wires under general anesthesia. Systematic outpatient adjustment of
stimulation parameters (active contacts, amplitude, duration, frequency) and frequent follow-ups are necessary,
especially during the first 6-12 months after implantation. The rates of surgical complications are quite variable and include intracranial hemorrhage, infections,
and rarely stroke, lead erosion and lead migration.
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From the psychiatric point of view, there is a risk of
developing manic or hypomanic symptoms, anxiety, or
worsening depression, but those symptoms are in general transient and respond to modification in parameters
of stimulation. Suicides have been reported in patients
with movement disorders and depression implanted with
DBS at different targets.
DBS in treatment-resistant patients requires a dedicated multidisciplinary team of neurosurgeons, psychiatrists, neuropsychologists and support staff. The
estimated cost of the implant is approximately $200,000
-$250,000, including device implantation and hospital
stay but not including preoperative assessments, travel
expenses, or costs possibly related to surgical complications. Replacements of the batteries add to the total burden for the patient, being necessary every 12-24 months
on average, with an estimated cost of approximately
$95,000 each time for hardware replacement and surgery. It is difficult to estimate the total additional cost of
the sessions necessary to adjust the parameters, between
$350 and $650 with an initial frequency of every two
weeks, then every month on average for the first year. A
more comprehensive evaluation of costs of DBS in
patients with Parkinson’s disorder outlined the importance of using broader outcome measures of quality of
life to calculate the true impact of DBS on patients and
their caregivers [58].
DBS Efficacy IN TRD
To our knowledge, preliminary double-blind, randomized,
sham-controlled studies are being conducted for two targets, SC25 and VC/VS, and the results have not been published yet. In literature, open-label studies have been
published for three targets: SC25, VC/VS and NAC.
1. SCG25
The early open-label study recruited 20 patients [59]
with an MDE and a level of treatment-resistance of 4
or 5. For this cohort, the follow-up has reached a
mean duration of 42 months [60]. The percentage of
patients who responded was 62.5% after 1 year, 46.2%
after 2 years, 75.0% after 3 years, and 64.3% at last
follow-up visit. Remission rates over time also
remained consistent with rates of 18.8% after year 1,
15.4% after year 2, 50% after year 3, and 42.9% at last
follow-up visit. More recently, a Spanish group
published the results of another independent openlabel trial of DBS implanted at SCG25 in 8 patients
with a level of TRD of 5 [61]. In this sample, the
response and remission rates were respectively 87.5%
and 37.5% at 6 months and 62.5% and 50% at one year.
2. VC/VS
In a sample of 26 patients with intractable OCD who
received VC/VS DBS treatment, the majority also
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had comorbid depression. In this cohort, after 36
months of VC/VS DBS stimulation, average HAM-D
scores decreased by 43.2%, and 14 of the 26 patients
met criteria for remission. Based on previous
experience with OCD patients[62], an open-label,
multicentric trial of VC/VS DBS for severe TRD was
conducted with 15 patients with level of treatment
resistance of 5 and mean duration of illness of
21 ± 11 years [63]. The results were extremely
positive, with response rates of 40% at 6 months and
53.3% at 24 months, while remission rates were
respectively 20% and 40%. In general, the DBS
treatment was well tolerated, and no patients
withdrew from the study.
3. NAC
In 2008, Schlaepfer and colleagues described bilateral
implantation in the shell and core of the NAC in 3
patients with TRD [64]. In 2010, the same group
published the results for open-label 1-year study
including 10 patients [65]. All of the patients enrolled
in the study had a history of recurrent or chronic
TRD and a high level of treatment-resistance. The
results were similar to those obtained with DBS at
other targets, with 50% of the patients reaching the
threshold for response at 12 months.
DBS summary
DBS for TRD is an experimental area of investigation.
Given the elevated costs and the risks related to the surgical procedure, DBS has been limited to the most
treatment-refractory cases of depression. The data on
efficacy in TRD are limited to a series of open-label studies, and rigorous double-blind trials are being conducted
to establish its role in the management of patients with
moderate to severe illness. DBS is not a treatment indicated for acute worsening, as the effects of stimulation
can take weeks to months to manifest. Moreover the
interactions between stimulation and medications need to
be carefully managed. In the case of relapse, DBS can be
combined successfully with previously ineffective antidepressant treatments, including medications, ECT and
psychotherapies.
Review and conclusions
Treatment-resistant depression has been associated with
poor clinical outcomes, impaired long- term social functioning, and high rates of medical comorbidity and
mortality.
Device-based therapy can be successfully integrated
into the algorithm for management of TRD, in conjunction with the continuation of antidepressant regimens.
Each device has specific indications according to the
level of the patient’s treatment resistance. A summary of
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Table 1 Comparison of devices for Treatment Resistant Depression (TRD). ECT : Electroconvulsive Therapy; TMS
Transcranial Magnetic Stimulation; VNS : Vagal Nerve Stimulation, DBS; Deep Brain Stimulation
FDA status
ECT
TMS
VNS
DBS
“Gold standard” in TRD
Approved for TRD after
failure of one AD
Approved
Not approved – under
investigation
Yes
Few cases
No
No
General anesthesia
no
Yes
Yes
yes
yes
No
no
10-15,000 for 3-4 weeks
6-12,000 for 3-4 weeks
40-45,000 for
surgery + device
200-250,000 for
surgery + device
200-800
200-400
350-620
350-620
Reimbursed by insurance
Requires surgery/multidisciplinary team
Acute clinical efficacy
Approximate costs (USD)
Follow-up adjustments /
maintenance (per visit, USD)
the features of each device as compared to ECT is presented in Table 1.
TMS is safe and well tolerated, and it has been
approved by the FDA for adults with depression who
have failed to respond to one antidepressant. Given its
favorable side effect profile, it may also be indicated for
patients who are intolerant of medications. Its use in
TRD is currently not firmly supported by clinical trials.
VNS and DBS have much higher costs and require a
surgical approach; therefore they have been utilized primarily in patients with high, or extremely high, level of
treatment-resistance, usually after the patient has failed
a course of ECT. VNS has a well-established safety record deriving from its use in the treatment of epilepsy; it
is FDA-approved for TRD and appears to be most effective in patients with MDD or bipolar disorder with low
to moderate, but not extreme, antidepressant resistance.
DBS for TRD is an experimental area of investigation for
which the optimal neuroanatomical targets and stimulation
parameters have yet to be determined. Given the elevated
costs and the risks related to surgical implantation, DBS
has been utilized in the most treatment-refractory cases.
Future directions for the clinical development of TMS involve designing double-blind randomized controlled trials
of augmentation of antidepressant therapy in patients who
are drug-naïve or have moderate depression severity and
designing protocols for long-term maintenance. For VNS,
papers about its long-term benefits and limited adverse
effects are being published, but it is unclear whether more
controlled trials in depression will be pursued. For DBS, a
series of open-label studies on DBS for TRD have been
published, and double-blind research trials are underway.
As the number of patients treated with new devices
increases, the ideal candidates and target population for
each device will likely be established.
Competing interest
The author(s) declare that they have no competing interests.
Authors’ contributions
Dr. Dougherty receives funding from Medtronic (research and consulting/
honoraria), Northstar (research), and Cyberonics (research).
CC and DD participated to the review of the literature and drafting of the
manuscript. All authors read and approved the final manuscript.
Acknowledgments
The authors thank Alexandra Rodman and Trina Chang, MD for the help in
reviewing the manuscript.
Received: 1 March 2012 Accepted: 24 July 2012
Published: 17 August 2012
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